The NLR (nucleotide-binding domain, leucine-rich repeat protein, also known as NOD-like receptor) family is a group of cytosolic proteins that detect intracellular microbes. Within this gene family, the N0D2 gene has received the most attention due its genetic association with inflammatory bowel disease (IBD). Furthermore, we and others have shown that inflammasome-associated NLRs such as NLRP3 and NLRP6, as well as inflammasome components can protect against experimental colitis and alter the microbiome, indicating a more expanded relevance of this family with colitis. Most recently a subgroup of NLRs is found to inhibit NFkappaB activation and impact experimental colitis. We and others showed that NLRP12 reduces colitis by suppressing NF-kappaB activation. This indicates for the first time that NLRs can attenuate colitis by negatively impacting NF-kappB. NLRP12 suppresses inflammation by causing the proteasome-mediated degradation of NIK (NF-kappaB inducing kinase), which is critical for non-canonical NF-kappaB activation. Others have shown that NLRP12 negatively impacts the canonical NF-kappaB. Furthermore both groups showed that NLRP12 downregulates MAP kinases, and the presence of NLRP12 attenuates ERK phosphorylation. In addition to NLRP12 we have recently identified NLRC3 as another member that inhibits TLR signaling by reducing K63- ubiquitination of TRAF6 and preventing canonical NF-kappa kappa activation. This inhibition of NF-kappa kappa is accompanied by attenuated LPS response. This project will assess the roles and mechanisms by which these two anti-inflammatory NLRs affect a number of colitis models and profile the expression of these proteins and their downstream effects in samples from colitis patients vs. controls.